While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. ...Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from ...developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high‐resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1‐asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.
Ancillary studies facilitate accurate diagnosis of morphologically challenging mesothelial proliferations. The current diagnostic algorithm proceeds from BAP1 immunohistochemistry to CDKN2A ...fluorescence in situ hybridization. While MTAP immunohistochemistry has recently shown promise as a surrogate for CDKN2A fluorescence in situ hybridization, it has been examined in only a few single-institution studies. Furthermore, there are no published reports on interobserver agreement or interlaboratory reproducibility for MTAP immunohistochemistry. We performed MTAP immunohistochemistry on 20 benign mesothelial lesions and 99 malignant mesotheliomas from five mesothelioma centers in four countries, and each MTAP stain was independently interpreted by four pathologists. CDKN2A fluorescence in situ hybridization data were available for a subset of cases, and a subset of cases was subjected in MTAP immunohistochemistry in multiple laboratories to assess interlaboratory reproducibility. Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82). Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77-0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion. MTAP immunohistochemistry is a reliable surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant mesothelioma. Interobserver agreement is excellent for interpretation of MTAP staining, and protocols performed in different laboratories yield concordant MTAP staining results. Rare cases with immunohistochemical MTAP loss may retain normal CDKN2A copy number, and the MTAP staining results should be correlated with clinicopathologic findings and other ancillary studies.
Pleural mesothelioma classification update Beasley, Mary Beth; Galateau-Salle, Francoise; Dacic, Sanja
Virchows Archiv : an international journal of pathology,
2021/1, Letnik:
478, Številka:
1
Journal Article
Recenzirano
The 2015 WHO classification of pleural mesotheliomas includes three major histologic subtypes—epithelioid, sarcomatoid, and biphasic. Recent genomic data has supported the need for a more granular ...and clinically valid classification beyond the three current subtypes. Because of tumor rarity and overlapping histologic features with other tumor types, diagnostic immunohistochemical work up is essential component in establishing the final diagnosis of mesothelioma. The use of BAP1 and
CDKN2A
/MTAP improves the diagnostic sensitivity of effusion specimens and are valuable in establishing the diagnosis of epithelioid mesothelioma. The major change in the forthcoming WHO classification is the inclusion of mesothelioma in situ as a diagnostic category. In this review, we discuss recently proposed changes in the histologic classification of pleural mesothelioma, differential diagnosis, and importance of ancillary diagnostic studies.
The existence of an in situ phase of malignant mesothelioma has long been postulated but until recently has been impossible to prove. Here we describe ten patients with mesothelioma in situ, defined ...by a single layer of surface mesothelial cells showing loss of BAP1 nuclear immunostaining, no evidence of tumor by imaging and/or by direct examination of the pleura/peritoneum, and no invasive mesothelioma developing for at least 1 year. Nine cases were pleural and one peritoneal. Most patients were biopsied for repeated effusions of unknown etiology; in two patients mesothelioma in situ was found incidentally in lung cancer resections. In addition to surface mesothelium with BAP1 loss, one case had a surface papillary proliferation with BAP1 loss, and two cases had a small (few millimeter) nodule with BAP1 loss. CDKN2A was deleted by FISH in one of eight cases. Methylthioadenosine phosphorylase showed partial loss in the surface mesothelium by immunohistochemistry in three cases. Invasive malignant mesothelioma developed in seven patients with time between biopsy and invasive disease from 12 to 92 (median 60) months. Invasive mesothelioma has not developed in the other three patients at 12, 57, and 120 months, but the latter patient, who has pleural plaques, still has repeated pleural effusions, probably representing a so-called "benign asbestos effusion." We conclude that mesothelioma in situ, as diagnosed using the criteria outlined above, is associated with a high risk of developing invasive mesothelioma, but typically over a relatively protracted time, so that curable interventions maybe possible.
- Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose.
- To provide updated, practical guidelines for the pathologic diagnosis of MM.
- Pathologists involved in the ...International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks.
- There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Aims
Mesothelioma is a rare malignancy of the serosal membranes that is commonly related to exposure to asbestos. Despite extensive research and clinical trials, prognosis to date remains poor. ...Consistent, comprehensive and reproducible pathology reporting form the basis of all future interventions for an individual patient, but also ensures that meaningful data are collected to identify predictive and prognostic markers.
Methods and results
This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the international consensus mesothelioma reporting data set. It describes the ‘core’ and ‘non‐core’ elements to be included in pathology reports for mesothelioma of all sites, inclusive of clinical, macroscopic, microscopic and ancillary testing considerations. An international expert panel consisting of pathologists and a medical oncologist produced a set of data items for biopsy and resection specimens based on a critical review and discussion of current evidence, and in light of the changes in the 2021 WHO Classification of Tumours. The commentary focuses particularly upon new entities such as mesothelioma in situ and provides background on relevant and essential ancillary testing as well as implementation of the new requirement for tumour grading.
Conclusion
We recommend widespread and consistent implementation of this data set, which will facilitate accurate reporting and enhance the consistency of data collection, improve the comparison of epidemiological data, support retrospective research and ultimately help to improve clinical outcomes. To this end, all data sets are freely available worldwide on the ICCR website (www.iccr‐cancer.org/data‐sets).
The International Collaboration on Cancer Reporting (ICCR) has developed an international consensus mesothelioma reporting data set which takes into account the recent updates to the WHO classification.
A new World Health Organization (WHO) Classification of Tumors of the Pleura has recently been published. While the histologic classification of pleural malignant mesothelioma remains the same in the ...2015 WHO classification as it was in the 2004 classification, multiple new observations have been recorded. First, more detailed study has been performed of histologic subtyping of epithelioid mesothelioma. In particular, it has been recognized that the pleomorphic subtype is associated with a poor prognosis, similar to that of sarcomatoid malignant mesothelioma. Second, there is improved understanding of the role of immunohistochemistry in distinguishing mesothelioma from carcinomas of various sites. Third, the criteria for distinguishing malignant mesothelioma from reactive mesothelial proliferations has been further refined. Fourth, additional studies of sarcomatoid mesothelioma have defined the frequency and spectrum of various histologic and immunohistochemical features, including heterologous elements. Finally, pleural well-differentiated papillary mesotheliomas are better defined and cases with invasive foci are recognized. In addition, several promising observations in mesothelioma pathology and genetics have been made in the past decade. These are now the subject of further investigation to determine if they can be validated in ways that will significantly impact clinical practice. These include a preliminary study of grading, suggesting that nuclear atypia and mitotic count are independent prognostic markers. The discovery of inactivating mutations in the BRCA1-associated protein 1 gene in sporadic and hereditary mesothelioma has opened up a variety of novel molecular, clinical, and diagnostic investigations. One possible diagnostic application includes the setting of separating mesothelioma from reactive mesothelial proliferations, where it may play a role in conjunction with p16 FISH. Another useful discovery was that the NAB2–STAT6 fusion is characteristic of solitary fibrous tumors. This led to development of a STAT6 antibody that is a reliable immunohistochemical marker for solitary fibrous tumors. Genetic studies also led to the finding that WWTR1–CAMTA1 fusions are useful diagnostic markers for epithelioid hemangioendotheliomas, which can present as pleural-based masses. Finally, desmoid type fibromatosis, a locally aggressive tumor that can present in the pleura, has been shown to frequently have CTNNB1 gene mutations and express β-catenin by immunohistochemistry.
The separation of benign from malignant mesothelial proliferations is crucial to patient management but is often a difficult problem for the pathologist.
To review the pathologic features that allow ...separation of benign from malignant mesothelioma proliferations, with an emphasis on new findings.
Literature review and experience of the authors.
Invasion is still the most reliable indicator of malignancy. The distribution and amount of proliferating mesothelial cells are important in separating benignity from malignancy, and keratin stains can be valuable because they highlight the distribution of mesothelial cells. Hematoxylin-eosin examination remains the gold standard, and the role of immunochemistry is extremely controversial; we believe that at present there is no reliable immunohistochemical marker of malignancy in this setting. Mesothelioma in situ is a diagnosis that currently cannot be accurately made by any type of histologic examination. Desmoplastic mesotheliomas are characterized by downward growth of keratin-positive spindled cells between S100-positive fat cells; some cases of organizing pleuritis can mimic involvement of fat, but these fat-like spaces are really S100-negative artifacts aligned parallel to the pleural surface. Fluorescence in situ hybridization on tissue sections to look for homozygous p16 gene deletions is occasionally useful, but many mesotheliomas do not show homozygous p16 deletions. Equivocal biopsy specimens should be diagnosed as atypical mesothelial hyperplasia and another biopsy requested if the clinicians believe the process is malignant.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
•Early mesothelioma diagnosis is challenging, especially on cytology.•Pleural effusions offer a useful resource of mesothelial cells for diagnosis.•BAP1 and CDKN2A losses are diagnostically relevant ...molecular alterations.•IHC and FISH improve diagnosis in all sample types but need validation.•Analysis of gene expression profiles may improve diagnosis.
Pathology plays an important role in diagnosing mesothelioma since radiological and clinical findings alone cannot distinguish mesothelioma reliably from its many mimics. The long-held gold standard for pathological diagnosis requires a tissue biopsy that, in addition to mesothelial phenotype, demonstrates invasion, but this is challenged by the WHO recognition of mesothelioma in situ (MIS) and concurrent acknowledgement of all mesotheliomas as malignant. Tumor sampling and ancillary techniques are of paramount importance for diagnosis of MIS. Standardisation of these techniques, cut-off points and terminology, and an updated staging system are urgently required. These clinically relevant issues and the impact of new developments were illustrated at the pathology session of 15th meeting of the International Mesothelioma Interest Group. It was reported that combination of losses in p16 nuclear expression, with cut-off ≤ 1%, and cytoplasmic MTAP with cut-off ≥ 30% demonstrated increased specificity (96%) and high sensitivity (86%) for CDKN2A HD detection. Otherwise, the combination of p16 IHC and CDKN2A HD may improve prognosis. The potential usefulness of pleural effusions for early diagnosis was demonstrated in a retrospective study investigating pleural effusions had been diagnosed as benign prior to mesothelioma diagnosis. Alterations of BAP1 (IHC) and CDKN2A (FISH) were detectable 2 or more years prior diagnosis. Moreover, analysis of gene expression profiles in cytology samples by principal component analysis discriminated reactive hyperpasia from epitheliod mesothelioma. Early diagnosis, including cytology diagnosis, is being acyively investigated. Since no treatment recommendations exist for MIS, pathologists recognise the need for international collaborations to fully characterise this rare entity. Clear communication with the clinical teams is required to ensure optimum patient care. The data reported in this meeting are encouraging and open avenues for further work that will allow even earlier diagnosis and better characterisation of mesothelioma progression, based on changes in gene expression, including epigenetic changes.
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